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  • br Materials and methods br Results br Discussion br Conclus

    2024-06-11


    Materials and methods
    Results
    Discussion
    Conclusions These studies provide important mechanistic insights to explain the long-established physiological observation that obese adipose tissue has higher rates of basal lipolysis. Increased lipolysis contributes to increased hepatic Ciclopirox ethanolamine synthesis production, hyperglycemia and type 2 diabetes. Obesity-induced inflammation and cytokine signaling increases ERK kinase activation and ERK substrate phosphorylation. In obesity, ERK phosphorylates β3AR in adipose tissue at S247 to increase rates of lipolysis (Figure 6A). The elevated flux of fatty acids adversely affects whole body insulin sensitivity [72]. Therapeutic efforts to decrease adipose tissue inflammation, lipolysis or MEK/ERK signaling would likely contribute to improved insulin resistance and decreased severity of type 2 diabetes.
    Author contributions S.H. and A.S.B. devised the project, designed and performed experiments, and analyzed data. W.S. and N.P. performed fly work and assisted with manuscript preparation. P.H.Z. and B.L. assisted with sample preparation for in vitro and in vivo experiments; M.P.J, J.S., and S.P.G., designed, performed, and analyzed mass spectrometry phosphoproteomics experiments. A.I.M., Z.D., and D.C. performed indirect calorimetry experiments and assisted with analysis. J.A.H. and C.J.P. assisted with experimental interpretation; H.A., A.T., and L.L. provided human tissue and regulatory assistance. A.S.B. and S.H. wrote the manuscript with input from all authors.
    Acknowledgements We thank Jeffrey Flier, Terry Maratos-Flier, Linus Tsai, and Evan Rosen for helpful discussions. Work in the Banks lab is supported by NIH DK093638 and DK107717. Work in the Perrimon lab is supported by NIH 5P01CA120964-04, NIH R01AR057352, American Diabetes Association (1-16-PDF-108), and the Howard Hughes Medical Institute. Calorimetry studies in the Brigham and Women's Metabolic Core are supported in part by the Harvard Digestive Disease CenterP30DK034854.
    Introduction Adrenergic receptors (ARs) are cell membrane receptors belonging to the seven-transmembrane-spanning G-protein coupled receptor superfamily. ARs respond to the sympathetic neurotransmitter noradrenaline and to the hormone adrenaline (in addition to various exogenous agonists) by producing a response within the cell that involves second messengers or ion channels. Molecular cloning has definitively identified the existence of three α1-AR subtypes: α1A, α1B and α1D; three α2-AR subtypes: α2A, α2B and α2C; and three β-AR subtypes: β1, β2 and β3 [1]. α-AR agonists are sympathomimetic agents that function through receptor excitatory functions and decrease resistance to airflow by decreasing the volume of nasal mucosa. Such decongestants are commonly used in the treatment of rhinitis. Additionally, β-AR agonists (particularly β2-AR agonists) have been widely used as bronchodilators for the treatment of asthma, and few studies have examined the role of β-AR in the nose. However, some reports have suggested the clinical benefits of β2-AR agonists in the treatment of nasal allergies [2], [3], [4]. To date, only two reports have described the distribution of human AR subtypes at mRNA level in nasal structures using in situ hybridization [5], [6]. No reports have described the distribution of AR subtypes in nasal structures at the protein level. Therefore, because of the recent availability of subtype-specific antibodies for α-AR and β-AR, we carried out the present study to examine the distribution of AR subtypes using immunohistochemical analysis in human nasal turbinate tissue.
    Materials and methods
    Results As shown in Fig. 1A, the immunoreactivity of α1A-AR was densely distributed in vascular smooth muscle. Epithelial cells, endothelial cells and submucosal glands were sparsely labeled. The basal cell layers were moderately labeled. In contrast, immunoreactivity for β2-AR was densely distributed in submucosal glands, while epithelial cells, endothelial cells and vascular smooth muscle were moderately labeled (Fig. 1B). As shown in Fig. 2A, immunoreactivity for α1D-AR was densely distributed in epithelial cells and submucosal glands, while endothelial cells were sparsely labeled. In contrast, immunoreactivity for α2C-AR was densely distributed in vascular smooth muscle, while epithelial cells and endothelial cells were sparsely labeled. There was no specific labeling in submucosal glands (Fig. 2B). The high power field images showed both cytoplasmic and membrane staining of these adrenergic receptors (Fig. 1, Fig. 2). The specificity of the staining was also confirmed by the absence of labeling with normal mouse IgG1 (Fig. 1C) and the rabbit immunoglobulin fraction (Fig. 2C).